This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Chemicals in the environment, including pollutants, prescription drugs, and dietary ingredients have a dramatic effect on the physiology of the body by changing the biochemical makeup of many cell types. These foreign compounds, collectively called xenobiotics, alter the suite of enzymes present in cells through induced changes in the regulation of gene expression. Central players in this induction are the so-called "xenobiotic-sensing" receptors which are members of the nuclear receptor (NR) superfamily of ligand-regulated transcription factors. Members of the NR1 subfamily of NRs directly link the presence of toxins to the production of phase I and II metabolizing enzymes and drug transporters responsible for xenobiotic detoxification and efflux. The structure of these NRs, possessing both ligand and DNA binding domains, reflects their function: xenobiotic binding, receptor translocation, and target gene transcriptional activation. Yet, increasing evidence suggests that the molecular pathway of xenosensation is hardly this simple. Crosstalk between xenosensing NRs, NRs mediating other signaling events, and even non-NR transcriptional regulators demonstrates the intersection of xenosensation with other physiologies such as lipid and carbohydrate metabolism and hormonal signaling. How does the biochemical removal environmental contaminants and chemotherapeutic agents impact the normal biochemistry of cells? Reciprocally, how does normal cellular biochemistry impact the clearance of xenobiotics? We propose that the combinatorial control of detoxification by NRs greatly broadens the known biology of these important chemical sensors. A complete understanding of the connections between xenobiotic detoxification and other cellular biochemistry is required to fully understand how drugs and environmental contaminants impact human health.